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TRPM7 is regulated by halides through its kinase domain

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Abstract

Transient receptor potential melastatin 7 (TRPM7) is a divalent-selective cation channel fused to an atypical α-kinase. TRPM7 is a key regulator of cell growth and proliferation, processes accompanied by mandatory cell volume changes. Osmolarity-induced cell volume alterations regulate TRPM7 through molecular crowding of solutes that affect channel activity, including magnesium (Mg2+), Mg-nucleotides and a further unidentified factor. Here, we assess whether chloride and related halides can act as negative feedback regulators of TRPM7. We find that chloride and bromide inhibit heterologously expressed TRPM7 in synergy with intracellular Mg2+ ([Mg2+]i) and this is facilitated through the ATP-binding site of the channel’s kinase domain. The synergistic block of TRPM7 by chloride and Mg2+ is not reversed during divalent-free or acidic conditions, indicating a change in protein conformation that leads to channel inactivation. Iodide has the strongest inhibitory effect on TRPM7 at physiological [Mg2+]i. Iodide also inhibits endogenous TRPM7-like currents as assessed in MCF-7 breast cancer cells, where upregulation of SLC5A5 sodium-iodide symporter enhances iodide uptake and inhibits cell proliferation. These results indicate that chloride could be an important factor in modulating TRPM7 during osmotic stress and implicate TRPM7 as a possible molecular mechanism contributing to the anti-proliferative characteristics of intracellular iodide accumulation in cancer cells.

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Acknowledgments

Expert technical expertise provided by Stephanie Johne and Christopher Maggio. Thank you to Dr. René J.M. Bindels and Dr. Alexey Ryazanov for kindly providing pCINeo-IRES-GFP-hTRPM6 construct. This work was supported by the National Institute for General Medical Science at the National Institutes of Health [P01GM078195 to A.F.].

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All authors declare no conflict of interests.

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  1. Annette Lis

    Present address: Institute of Biophysics, University of Homburg, 66421, Homburg, Germany

Authors and Affiliations

  1. Center for Biomedical Research, The Queen’s Medical Center, 1301 Punchbowl St., Honolulu, HI, 96813, USA

    Haijie Yu, Zheng Zhang, Annette Lis, Reinhold Penner & Andrea Fleig

  2. University of Hawaii Cancer Center & John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96813, USA

    Haijie Yu, Zheng Zhang, Annette Lis, Reinhold Penner & Andrea Fleig

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Correspondence to Andrea Fleig.

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H. Yu and Z. Zhang contributed equally to this work.

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Yu, H., Zhang, Z., Lis, A. et al. TRPM7 is regulated by halides through its kinase domain. Cell. Mol. Life Sci. 70, 2757–2771 (2013). https://doi.org/10.1007/s00018-013-1284-6

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